SUMMARY Sepsis is a medical condition caused by an overwhelming systemic inflammatory response to infection. Although the underlying infection can now be efficiently treated with antibiotics, there are no effective therapies to control the organ damage caused by the inflammatory response of the host. As a result, sepsis is the leading cause of mortality in intensive care units and is the tenth leading cause of death overall in the US. CD73 or ecto-5'-nucleotidase is a cell surface-associated anti-inflammatory enzyme. It has multiple anti- inflammatory actions, which are mediated by triggering the production of the anti-inflammatory agent adenosine. Using CD73 deficient mice and pharmacological antagonists, we have discovered that endogenous CD73 protects mice against polymicrobial sepsis-induced inflammation, organ damage, and mortality. Based on these results, we propose exogenously administered human recombinant soluble CD73 (hsCD73) as a novel and effective therapy for sepsis. Our hypothesis is that treatment of mice with human recombinant soluble CD73 would reduce inflammation, organ damage, and mortality in sepsis. To address this hypothesis, we propose two Specific Aims. In Specific Aim 1, we will test the efficacy of hsCD73 in preventing mortality in polymicrobial sepsis induced by cecal ligation and puncture in mice. In Specific Aim 2, we will delineate the effect of hsCD73 on inflammation and organ injury in sepsis. We expect that hsCD73 will reduce inflammation, organ damage, and mortality in septic mice. The long-term goal of this study is to develop hsCD73 as a safe and effective treatment option for the management of patients with sepsis.